2.9 CONCLUSION
2.10.1 MATERIALS AND METHODS
2.10.2.1 PREPARATION PARENT VINYLOGOUS ESTER 147
O
i-BuO 147 O 1. TMSCl, Et3N, NaI
CH3CN, 23 °C 2. Cl2CHCOCl, Et3N
hexanes, 23 °C H
TMSO Cl Cl
O
3. Zn, AcOH, H2O i-PrOH, –10!23 °C 4. PPTS (1.5 mol %) i-BuOH, PhCH3 reflux, Dean–Stark 66% yield, 4 steps 190
Vinylogous ester 147. NaI (157 g, 1.05 mol, 1.25 equiv) was placed in a 3 L 3-neck round-bottom flask, dried under high vacuum at 90 °C for 12 h, and allowed to cool to ambient temperature under N2. CH3CN (1.3 L) was added to dissolve the NaI. To the solution was added cyclopentanone (74.3 mL, 0.84 mol, 1.00 equiv), followed by Et3N (146 mL, 1.05 mol, 1.25 equiv). The flask was fitted with an addition funnel, and the funnel was charged with TMSCl (122 mL, 0.96 mmol, 1.14 equiv), which was added dropwise over 30 min. The resulting suspension was stirred for an additional 1 h at ambient temperature. Pentane (1.0 L) was added, and the biphasic system was stirred vigorously for 10 min. The phases were separated and the CH3CN layer was extracted with pentane (3 x 400 mL). The combined pentane phases were washed with H2O (2 x 500 mL) and brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product (131 g, quantitative) as a colorless oil.
A portion of the above trimethylsilyl ether (89.7 g, 0.57 mol, 1.00 equiv) was placed in a 3 L 3-neck round-bottom flask fitted with a stopper, an addition funnel, and an overhead stirrer. Hexanes (900 mL) was added, followed by Et3N (111 mL, 0.80 mol, 1.39 equiv). Dichloroacetyl chloride (66.4 mL, 0.69 mol, 1.21 equiv) was dissolved in hexanes (400 mL) and added dropwise over 9.5 h. After 18 h of stirring at ambient
87 temperature, the brown suspension was filtered, rinsing with EtOAc (3 x 500 mL). The clear brown solution was concentrated under reduced pressure and then filtered through a pad of Al2O3 (7 x 18 cm, neutral) using EtOAc as eluent. The solution was concentrated under reduced pressure to afford the desired product (125 g, 0.47 mol, 82% yield) as a brown oil that crystallized in the freezer (–20 °C).
A portion of the above dichlorocyclobutanone (53.4 g, 0.20 mol, 1.00 equiv) was placed in a 3 L 3-neck round-bottom flask fitted with a thermometer, an addition funnel, and an overhead stirrer. Isopropyl alcohol and purified water (170 mL each) were added and the suspension was cooled to –10 °C (internal temperature) using a MeOH/ice bath.
Zn dust (58.8 g, 0.90 mol, 4.50 equiv) was added in four portions (5 min between each) and AcOH (63 mL, 1.10 mol, 5.50 equiv) dissolved in H2O (130 mL) was added dropwise while keeping the internal temperature below 0 °C (usually added over 1.5 h).
The reaction was stirred for an additional 30 min at –10 °C (internal temperature) before the cooling bath was removed and the reaction was allowed to warm to ambient temperature. After 8.5 h, the reaction was filtered, rinsing with isopropyl alcohol (100 mL). The mixture was cooled to 0 °C and neutralized by portionwise addition of K2CO3
(74.6 g, 0.54 mol, 5.50 equiv). The viscous suspension was filtered, rinsing with H2O (100 mL) and EtOAc (300 mL). The biphasic system was concentrated under reduced pressure to ca. 200 mL and extracted with CH2Cl2. The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure to afford the desired product (24.2 g, 0.19 mol, 96% yield) as a pale orange oil.
To a solution of 1,3-cycloheptanedione (35.8 g, 0.28 mol, 1.00 equiv) in toluene (280 mL) in a 1 L flask fitted with a reflux condenser and Dean–Stark trap was added
88 isobutanol (208 mL, 2.27 mol, 8.11 equiv) and pyridinium p-toluenesulfonate (1.07 g, 4.26 mmol, 1.50 mol %). The solution was immersed in an oil bath at 130 °C and monitored by TLC. When the starting material was consumed (typically within 4–6 h), the reaction was allowed to cool to ambient temperature. The resulting dark orange solution was washed with sat. aqueous NaHCO3 (200 mL). The aqueous phase was extracted with EtOAc (3 x 150 mL) and the combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford a thick dark orange oil. The crude oil was flushed through a silica gel plug (SiO2, 7 x 9 cm, 1:4→3:7→1:1 Et2O-hexanes) to afford vinylogous ester 147 (43.5 g, 0.24 mol, 84%
yield, 66% yield over 4 steps) as a pale orange oil; Rf = 0.22 (2:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 5.37 (s, 1H), 3.49 (d, J = 6.6 Hz, 2H), 2.60–2.56 (m, 4H), 2.00 (sept, J = 6.6 Hz, 1H), 1.88–1.77 (m, 4H), 0.96 (d, J = 6.8 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 202.5, 176.6, 106.0, 75.0, 41.9, 33.1, 27.9, 23.7, 21.5, 19.3; IR (Neat Film NaCl) 2958, 2872, 1646, 1607, 1469, 1237, 1190, 1174 cm–1; HRMS (EI+) m/z calc'd for C11H18O2 [M]+•: 182.1307; found 182.1310.
2.10.2.2 PREPARATION OF β-KETOESTERS 148
O
i-BuO 148a
O O O
i-BuO 147
1. LDA, THF, –78 °C then
NC O
O 2. CH3I, Cs2CO3 CH3CN, 80 °C 79% yield, 2 steps
β-Ketoester 148a. To a solution of diisopropylamine (6.46 mL, 46.1 mmol, 1.20 equiv) in THF (180 mL) in a 500 mL round-bottom flask at 0 °C was added n-BuLi (17.2 mL,
89 44.2 mmol, 2.57 M in hexanes, 1.15 equiv) dropwise over 15 min using a syringe pump.
After 15 min of stirring at 0 °C, the mixture was cooled to –78 °C using an acetone/CO2(s) bath. A solution of vinylogous ester 147 (7.01 g, 38.4 mmol, 1.00 equiv) in THF (20 mL) was added dropwise over 20 min using a syringe pump. After an additional 1 h of stirring at –78 °C, allyl cyanoformate (4.60 mL, 42.2 mmol, 1.10 equiv) was added dropwise over 10 min. The mixture was stirred at –78 °C for 2.5 h, quenched by addition of sat. aqueous NH4Cl and H2O (30 mL each), and allowed to warm to ambient temperature. The reaction was diluted with Et2O (100 mL) and the phases were separated. The aqueous phase was extracted with Et2O (2 x 100 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure to afford a pale orange oil.
The crude oil was dissolved in CH3CN (130 mL) in a 500 mL round-bottom flask and treated with CH3I (7.2 mL, 115 mmol, 3.00 equiv) and Cs2CO3 (16.76 g, 49.9 mmol, 1.30 equiv). The flask was fitted with a condenser, immersed in an oil bath, and heated to 80
°C with vigorous stirring. After 12 h of stirring at 80 °C, the reaction was allowed to cool to ambient temperature, diluted with EtOAc (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford an orange oil. The crude product was purified by flash column chromatography (SiO2, 5 x 15 cm, 19:1→9:1 hexanes:EtOAc, dry-loaded using Celite) to afford β-ketoester 148a (8.51 g, 30.4 mmol, 79% yield over 2 steps) as a pale yellow oil; Rf = 0.43 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 5.86 (dddd, J = 17.1, 10.7, 5.6, 5.6 Hz, 1H), 5.39 (s, 1H), 5.29 (app dq, J = 17.1, 1.5 Hz, 1H), 5.20 (app dq, J = 10.5, 1.4 Hz, 1H), 4.62 (dddd, J = 13.3, 5.6, 1.2, 1.2 Hz, 1H), 4.56 (dddd, J = 13.4, 5.6, 1.2, 1.2 Hz, 1H), 3.54–3.42 (m, 2H), 2.59 (ddd, J = 17.8, 9.8,
90 3.9 Hz, 1H), 2.45–2.38 (m, 2H), 2.02–1.94 (m, 2H), 1.84–1.75 (m, 1H), 1.70 (ddd, J = 14.4, 7.3, 4.4 Hz, 1H), 1.43 (s, 3H), 0.94 (d, J = 6.6 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 199.1, 174.0, 173.5, 132.0, 118.4, 105.2, 74.8, 65.8, 59.1, 34.3, 33.9, 27.9, 24.2, 21.4, 19.3; IR (Neat Film NaCl) 2959, 2936, 2875, 1734, 1650, 1613, 1456, 1384, 1233, 1170, 1115, 994 cm–1; HRMS (EI+) m/z calc'd for C16H24O4 [M]+•: 280.1675; found 280.1686.
O
i-BuO 147
1. LDA, THF, –78 °C then
NC O
O 2. CH3CH2I, NaH THF, 0!55 °C 81% yield, 2 steps
O
i-BuO 148b
O O
β-Ketoester 148b. To a solution of diisopropylamine (0.92 mL, 6.58 mmol, 1.20 equiv) in THF (27 mL) in a 100 mL round-bottom flask at 0 °C was added n-BuLi (2.56 mL, 6.30 mmol, 2.46 M in hexanes, 1.15 equiv) dropwise over 10 min. After 15 min of stirring at 0 °C, the mixture was cooled to –78 °C using an acetone/CO2(s) bath. A solution of vinylogous ester 147 (1.00 g, 5.48 mmol, 1.00 equiv) in THF (2 mL) was added dropwise using positive pressure cannulation. After an additional 1 h of stirring at –78 °C, allyl cyanoformate (0.67 mL, 6.02 mmol, 1.10 equiv) was added dropwise over 10 min. The mixture was stirred at –78 °C for 2.5 h, quenched by addition of 50% sat.
aqueous NH4Cl (8 mL), and allowed to warm to ambient temperature. The reaction was diluted with Et2O (25 mL) and the phases were separated. The aqueous phase was extracted with Et2O (3 x 25 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a pale orange oil.
91 The crude oil was dissolved in THF (8 mL) in a 100 mL round-bottom flask, cooled to 0 °C, and stirred vigorously as hexane-washed NaH (158 mg, 6.58 mmol, 1.20 equiv) was added in one portion. Evolution of gas was observed and the reaction was stirred at 0 °C for 30 min to give a yellow-orange solution. CH3CH2I (1.31 mL, 16.4 mmol, 3.00 equiv) was added dropwise. The reaction was allowed to warm to ambient temperature and stirred for 4.5 h. The mixture was heated to 45 °C and stirred for 1.5 h. Additional CH3CH2I (0.65 mL, 8.22 mmol, 1.50 equiv) was added dropwise and the mixture was stirred at 45 °C for 6 h. A third portion of CH3CH2I (0.33 mL, 4.11 mmol, 0.75 equiv) was added dropwise and the reaction was warmed to 55 °C and stirred for 1.5 h. The flask was cooled to ambient temperature and quenched by addition of 50% sat. aqueous NH4Cl (10 mL). The phases were separated and the aqueous layer was extracted with Et2O (3 x 15 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 5 x 20 cm, 9:1→6:1→3:1→2:1 hexanes:EtOAc) to afford β-ketoester 148b (1.31 g, 4.44 mmol, 81% yield over 2 steps) as a yellow oil; Rf = 0.53 (4:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3) δ 5.85 (dddd, J = 17.5, 10.2, 5.7, 5.7 Hz, 1H), 5.35 (s, 1H), 5.29 (app dq, J = 17.2, 1.5 Hz, 1H), 5.19 (app dq, J = 10.4, 1.3 Hz, 1H), 4.62 (dddd, J = 13.2, 5.7, 1.4, 1.4 Hz, 1H), 4.54 (dddd, J = 13.2, 5.7, 1.4, 1.4 Hz, 1H), 3.57–3.34 (m, 2H), 2.60 (dddd, J = 17.9, 9.9, 3.7, 1.2 Hz, 1H), 2.49–2.26 (m, 2H), 2.12–1.85 (m, 4H), 1.85–1.57 (m, 2H), 0.93 (d, J = 6.7 Hz, 6H), 0.84 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 198.7, 173.7, 173.2, 132.0, 118.5, 105.5, 74.7, 65.7, 63.1, 34.1, 31.0, 30.6, 27.9, 22.0, 19.3, 9.0; IR (Neat Film NaCl) 3085, 2960, 2937, 2876, 1731, 1663, 1613, 1471, 1461, 1453, 1424, 1383,
92 1369, 1328, 1304, 1278, 1229, 1199, 1170, 1121, 1006, 988, 931, 875, 858, 813 cm–1; HRMS (MM: ESI-APCI+) m/z calc'd for C17H27O4 [M+H]+: 295.1904; found 295.1918.
O
i-BuO 147
1. LDA, THF, –78 °C then
NC O
O 2. PhCH2Br, NaH THF, 0!23 °C 88% yield, 2 steps
O
i-BuO 148c
Ph
O O
β-Ketoester 148c. To a solution of diisopropylamine (0.92 mL, 6.58 mmol, 1.20 equiv) in THF (27 mL) in a 100 mL round-bottom flask at 0 °C was added n-BuLi (2.56 mL, 6.30 mmol, 2.46 M in hexanes, 1.15 equiv) dropwise over 10 min. After 15 min of stirring at 0 °C, the mixture was cooled to –78 °C using an acetone/CO2(s) bath. A solution of vinylogous ester 147 (1.00 g, 5.48 mmol, 1.00 equiv) in THF (2 mL) was added dropwise using positive pressure cannulation. After an additional 1 h of stirring at –78 °C, allyl cyanoformate (0.67 mL, 6.02 mmol, 1.10 equiv) was added dropwise over 10 min. The mixture was stirred at –78 °C for 2.5 h, quenched by addition of 50% sat.
aqueous NH4Cl (8 mL), and allowed to warm to ambient temperature. The reaction was diluted with Et2O (25 mL) and the phases were separated. The aqueous phase was extracted with Et2O (3 x 25 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a pale orange oil.
The crude oil was dissolved in THF (8 mL) in a 100 mL round-bottom flask, cooled to 0 °C, and stirred vigorously as hexane-washed NaH (197 mg, 8.22 mmol, 1.50 equiv) was added in one portion. Evolution of gas was observed and the reaction was stirred at 0 °C for 30 min to give a yellow-orange solution. Benzyl bromide (1.96 mL, 16.44 mmol, 3.00 equiv) was added dropwise. The reaction was allowed to warm to ambient
93 temperature and stirred for 3 h. The reaction was quenched by addition of 50% sat.
aqueous NH4Cl (10 mL). The phases were separated and the aqueous layer was extracted with Et2O (3 x 15 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 3 x 23 cm, hexanes→10:1 hexanes:EtOAc) to afford β-ketoester 148c (1.72 g, 4.83 mmol, 88% yield over 2 steps) as a pale yellow oil; Rf = 0.26 (10:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3) δ 7.30–7.15 (m, 3H), 7.15–7.06 (m, 2H), 5.85 (dddd, J = 17.1, 10.4, 5.8, 5.8 Hz, 1H), 5.36 (s, 1H), 5.30 (app dq, J = 17.2, 1.5 Hz, 1H), 5.21 (app dq, J = 10.4, 1.3 Hz, 1H), 4.63 (dddd, J = 13.2, 5.7, 1.3, 1.3 Hz, 1H), 4.52 (dddd, J = 13.2, 5.8, 1.3, 1.3 Hz, 1H), 3.42 (d, J = 6.5 Hz, 2H), 3.30 (d, J = 13.5 Hz, 1H), 3.23 (d, J = 13.5 Hz, 1H), 2.54 (ddd, J = 12.1, 10.0, 3.5 Hz, 1H), 2.38–2.18 (m, 2H), 2.04–1.83 (m, 2H), 1.81–1.64 (m, 2H), 0.92 (d, J = 6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 198.0, 174.0, 172.7, 137.0, 131.8, 130.7, 128.1, 126.8, 118.8, 105.7, 74.8, 66.0, 64.0, 43.1, 34.0, 31.3, 27.9, 22.0, 19.2; IR (Neat Film NaCl) 3085, 3062, 3029, 2959, 2934, 2873, 1736, 1732, 1661, 1652, 1611, 1495, 1471, 1454, 1423, 1383, 1368, 1270, 1235, 1173, 1088, 1007, 957, 992, 930, 862, 815, 741 cm–1; HRMS (APCI+) m/z calc'd for C22H29O4 [M+H]+: 357.2060; found 357.2051.
O
i-BuO 147
1. LDA, THF, –78 °C then
NC O
O 2. propargyl bromide NaH, THF, 0!23 °C 83% yield, 2 steps
O
i-BuO 148d
O O
β-Ketoester 148d. To a solution of diisopropylamine (0.92 mL, 6.58 mmol, 1.20 equiv) in THF (27 mL) in a 100 mL round-bottom flask at 0 °C was added n-BuLi (2.56 mL,
94 6.30 mmol, 2.46 M in hexanes, 1.15 equiv) dropwise over 10 min. After 15 min of stirring at 0 °C, the mixture was cooled to –78 °C using an acetone/CO2(s) bath. A solution of vinylogous ester 147 (1.00 g, 5.48 mmol, 1.00 equiv) in THF (2 mL) was added dropwise using positive pressure cannulation. After an additional 1 h of stirring at –78 °C, allyl cyanoformate (0.67 mL, 6.02 mmol, 1.10 equiv) was added dropwise over 10 min. The mixture was stirred at –78 °C for 2.5 h, quenched by addition of 50% sat.
aqueous NH4Cl (8 mL), and then allowed to warm to ambient temperature. The reaction was diluted with Et2O (25 mL) and the phases were separated. The aqueous phase was extracted with Et2O (3 x 25 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a pale orange oil.
The crude oil was dissolved in THF (8 mL) in a 100 mL round-bottom flask, cooled to 0 °C, and stirred vigorously as hexane-washed NaH (197 mg, 8.22 mmol, 1.5 equiv) was added in one portion. Evolution of gas was observed and the reaction was stirred at 0 °C for 30 min to give a yellow-orange solution. Propargyl bromide (1.22 mL, 10.96 mmol, 80% wt in toluene, 2.00 equiv) was added dropwise and the reaction was allowed to warm to ambient temperature and stirred for 5.5 h. The reaction was quenched by addition of 50% sat. aqueous NH4Cl (10 mL). The phases were separated and the aqueous layer was extracted with Et2O (3 x 15 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was purified by flash column chromatography (SiO2, 3 x 24 cm, hexanes→20:1→15:1→10:1 hexanes:EtOAc) to afford β-ketoester 148d (1.38 g, 4.53 mmol, 83% yield over 2 steps) as a pale yellow oil; Rf = 0.55 (4:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3) δ5.85 (dddd, J = 17.2, 10.4, 5.7, 5.7 Hz, 1H), 5.38 (s, 1H), 5.29
95 (app dq, J = 17.2, 1.5 Hz, 1H), 5.19 (app dq, J = 10.4, 1.3 Hz, 1H), 4.63 (dddd, J = 13.2, 5.6, 1.4, 1.4 Hz, 1H), 4.56 (dddd, J = 13.2, 5.7, 1.4, 1.4 Hz, 1H), 3.56–3.38 (m, 2H), 2.79 (dd, J = 2.7, 0.6 Hz, 1H), 2.72–2.32 (m, 4H), 2.15–1.89 (m, 4H), 1.89–1.71 (m, 1H), 0.93 (d, J = 6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 196.5, 174.8, 171.7, 131.7, 118.7, 105.0, 80.2, 74.9, 71.4, 66.1, 62.0, 34.3, 31.2, 27.9, 27.5, 21.7, 19.2; IR (Neat Film NaCl) 3289, 3085, 2959, 2933, 2874, 2120, 1740, 1735, 1654, 1649, 1470, 1452, 1424, 1402, 1384, 1369, 1309, 1291, 1272, 1232, 1187, 1173, 1133, 1085, 1066, 1007, 968, 930, 863, 820 cm–1; HRMS (EI+) m/z calc'd for C18H25O4 [M+H]+: 305.1753; found 305.1746.
O
i-BuO 147
1. LDA, THF, –78 °C then
NC O
O 2. acrolein, Et3N CH2Cl2, 0!40 °C 77% yield, 2 steps
O
i-BuO 148k
O
i-BuO 148e KOt-Bu
MePh3PBr PhCH3 0!23 °C 79% yield H O
O
O
O
O
β-Ketoester 148k. To a solution of diisopropylamine (1.49 mL, 10.63 mmol, 1.20 equiv) in THF (43 mL) in a 250 mL round-bottom flask at 0 °C was added n-BuLi (4.74 mL, 10.19 mmol, 2.51 M in hexanes, 1.15 equiv) dropwise over 10 min. After 15 min of stirring at 0 °C, the mixture was cooled to –78 °C using an acetone/CO2(s) bath. A solution of vinylogous ester 147 (1.61 g, 8.86 mmol, 1.00 equiv) in THF (3 mL) was added dropwise using positive pressure cannulation. After an additional 1 h of stirring at –78 °C, allyl cyanoformate (1.06 mL, 9.74 mmol, 1.10 equiv) was added dropwise over 10 min. The mixture was stirred at –78 °C for 2.5 h, quenched by addition of 50% sat.
aqueous NH4Cl (12.9 mL), and then allowed to warm to ambient temperature. The reaction was diluted with Et2O (50 mL) and the phases were separated. The aqueous
96 phase was extracted with Et2O (3 x 100 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a pale orange oil. The crude oil was purified by automated flash column chromatography using a Teledyne Isco CombiFlash Rf (SiO2, 25 g loading cartridge, 330 g column, hold 0% [3 min]→ramp to 20% [10 min]→hold 20% [10 min]→ramp to 50% [4 min]→hold 50%
EtOAc in hexanes [5 min]) to afford the intermediate β-ketoester (2.02 g, 7.58 mmol, 86% yield).
A portion of the intermediate β-ketoester (990 mg, 3.72 mmol, 1.00 equiv) was dissolved in CH2Cl2 (10 mL) in a 100 mL round-bottom flask, cooled to 0 °C, and treated with Et3N (0.518 mL, 3.72 mmol, 1.00 equiv). Acrolein (0.248 mL, 3.72 mmol, 1.00 equiv) was added dropwise and the reaction was allowed to warm to ambient temperature. After 51 h, the reaction was cooled to 0 °C and an additional portion of acrolein (0.125 mL, 1.86 mmol, 0.50 equiv) was added. After 100 h, the reaction was concentrated under reduced pressure, dissolved in Et2O, and filtered through a cotton plug to remove salts. The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography (SiO2, 3 x 25 cm, 10:1→6:1→4:1 hexanes:EtOAc) to afford β-ketoester 148k (1.07 g, 3.34 mmol, 90% yield, 77% yield over 2 steps) as a clear oil; Rf = 0.23, broad (4:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3) δ9.73 (t, J = 1.3 Hz, 1H), 5.86 (dddd, J = 17.1, 10.4, 5.8, 5.8 Hz, 1H), 5.36 (s, 1H), 5.30 (app dq, J = 17.2, 1.5 Hz, 1H), 5.22 (app dq, J = 10.4, 1.2 Hz, 1H), 4.63 (dddd, J = 13.1, 5.7, 1.3, 1.3 Hz, 1H), 4.55 (dddd, J = 13.2, 5.8, 1.3, 1.3 Hz, 1H), 3.55–3.40 (m, 2H), 2.66–2.29 (m, 5H), 2.29–2.08 (m, 2H), 2.08–1.89 (m, 2H), 1.89–1.59 (m, 2H), 0.94 (d, J = 6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 201.6, 197.9, 173.9, 172.7, 131.7,
97 119.0, 105.3, 74.9, 66.0, 61.8, 39.7, 34.2, 32.1, 29.6, 27.9, 21.5, 19.2; IR (Neat Film NaCl) 3084, 2960, 2936, 2875, 2829, 2723, 1727, 1649, 1611, 1471, 1454, 1422, 1403, 1385, 1369, 1306, 1270, 1234, 1191, 1173, 1104, 1004, 990, 931, 877, 862, 822 cm–1; HRMS (FAB+) m/z calc'd for C18H27O5 [M+H]+: 323.1858; found 323.1860.
β-Ketoester 148e. MePh3PBr (1.33 g, 3.72 mmol, 1.26 equiv) was suspended in toluene (20 mL) in 100 mL round-bottom flask and cooled to 0 °C. KOt-Bu (0.348 g, 3.10 mmol, 1.05 equiv) was added in one portion and the bright yellow mixture was stirred at 0 °C for 30 min, warmed to ambient temperature, and stirred for an additional 2 h. The mixture was cooled to 0 °C and a solution of aldehyde 148k (0.95 g, 2.94 mmol, 1.00 equiv) in toluene (2 mL) was added to the reaction using positive pressure cannulation.
The mixture turned brown. The reaction was maintained at 0 °C for 1.5 h, warmed to ambient temperature, and stirred for 4 h. The reaction was quenched by addition of 50%
sat. aqueous NH4Cl (4 mL). The phases were separated and the aqueous phase was extracted with Et2O (3 x 100 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 3 x 25 cm, 20:1→15:1 hexanes:EtOAc) to afford β-ketoester 148e (747 mg, 2.33 mmol, 79% yield) as a pale yellow oil; Rf = 0.66 (4:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3) δ5.85 (dddd, J = 17.2, 10.4, 5.7, 5.7 Hz, 1H), 5.84–5.69 (m, 1H), 5.35 (s, 1H), 5.29 (app dq, J = 17.2, 1.5 Hz, 1H), 5.20 (app dq, J = 10.4, 1.3 Hz, 1H), 5.08–4.96 (m, 1H), 4.96–4.87 (m, 1H), 4.62 (dddd, J = 13.1, 5.7, 1.4, 1.4 Hz, 1H), 4.54 (dddd, J = 13.1, 5.7, 1.4, 1.4 Hz, 1H), 3.53–3.38 (m, 2H), 2.59 (dddd, J = 17.9, 9.8, 3.7, 1.1 Hz, 1H), 2.51–2.29 (m, 2H), 2.09–1.87 (m, 6H), 1.87–
98 1.66 (m, 2H), 0.94 (d, J = 6.7, 3H), 0.94 (d, J = 6.7, 3H); 13C NMR (75 MHz, CDCl3) δ 198.4, 173.7, 173.0, 138.2, 131.9, 118.6, 114.9, 105.4, 74.8, 65.8, 62.6, 36.8, 34.1, 31.5, 28.8, 27.9, 22.0, 19.3; IR (Neat Film NaCl) 3078, 2959, 2935, 2874, 1732, 1662, 1612, 1471, 1453, 1423, 1401, 1384, 1369, 1307, 1270, 1231, 1194, 1170, 1091, 993, 913, 874, 817, 766 cm–1; HRMS (EI+) m/z calc'd for C19H28O4 [M]+•: 320.1988; found 320.1977.
O
i-BuO 147
1. LDA, THF, –78 °C then
NC O
O
2. 1-chloro-2,4-pentadiene NaH, THF, 0!60 °C 84% yield, 2 steps
O
i-BuO 148f
O O
β-Ketoester 148f. To a solution of diisopropylamine (0.406 mL, 2.90 mmol, 1.20 equiv) in THF (12 mL) in a 50 mL round-bottom flask at 0 °C was added n-BuLi (1.10 mL, 2.77 mmol, 2.51 M in hexanes, 1.15 equiv) dropwise over 10 min. After 15 min of stirring at 0 °C, the mixture was cooled to –78 °C using an acetone/CO2(s) bath. A solution of vinylogous ester 147 (0.44 g, 2.41 mmol, 1.00 equiv) in THF (2 mL) was added dropwise using positive pressure cannulation. After an additional 1 h of stirring at –78 °C, allyl cyanoformate (0.288 mL, 2.65 mmol, 1.10 equiv) was added dropwise over 10 min. The mixture was stirred at –78 °C for 2.5 h, quenched by addition of 50% sat. aqueous NH4Cl (4 mL), and then allowed to warm to ambient temperature. The reaction was diluted with Et2O (15 mL) and the phases were separated. The aqueous phase was extracted with Et2O (3 x 15 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a pale orange oil. The crude oil was purified by automated flash column chromatography using a Teledyne Isco CombiFlash Rf (SiO2, 5 g loading cartridge, 40 g column, hold 0% [1 min]→ramp to 20% [8
99 min]→hold 20% [5 min]→ramp to 50% [4 min]→50% EtOAc in hexanes [6 min]) to afford the intermediate β-ketoester (590 mg, 2.21 mmol, 92% yield).
A portion of the intermediate β-ketoester (250 mg, 0.94 mmol, 1.00 equiv) was dissolved in THF (5 mL) in a 50 mL round-bottom flask, cooled to 0 °C, and stirred vigorously as hexane-washed NaH (33.8 mg, 6.58 mmol, 1.50 equiv) was added in one portion. Evolution of gas was observed and the reaction was stirred at 0 °C for 30 min to give a yellow-orange solution. 1-chloro-2,4-pentadiene53 (144 mg, 1.41 mmol, 1.50 equiv) was added dropwise and the reaction was allowed to warm to ambient temperature and then heated to 40 °C. After 10.5 h, an additional portion of 1-chloro-2,4-pentadiene (144 mg, 1.41 mmol, 1.50 equiv) was added and the reaction was heated at 50 °C for 11.5 h. The flask was cooled to ambient temperature and the reaction was quenched by addition of 50% sat. aqueous NH4Cl (2 mL). The phases were separated and the aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 3 x 25 cm, 20:1→15:1→10:1 hexanes:EtOAc) to afford β-ketoester 148f (286 mg, 0.86 mmol, 91%
yield, 84% yield over 2 steps) as a pale yellow oil; Rf = 0.59 (4:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3) δ6.25 (ddd, J = 16.7, 10.3, 10.3 Hz, 1H), 6.11–5.98 (m, 1H), 5.83 (dddd, J = 17.2, 10.4, 5.7, 5.7 Hz, 1H), 5.58 (ddd, J = 15.1, 7.7, 7.7 Hz, 1H), 5.36 (s, 1H), 5.27 (app dq, J = 17.2, 1.5 Hz, 1H), 5.18 (app dq, J = 10.4, 1.2 Hz, 1H), 5.08 (dd, J
= 16.9, 1.6 Hz, 1H), 4.96 (dd, J = 16.9, 1.6 Hz, 1H), 4.60 (dddd, J = 13.2, 5.8, 1.4, 1.4 Hz, 1H), 4.52 (dddd, J = 13.2, 5.8, 1.4, 1.4 Hz, 1H), 3.57–3.35 (m, 2H), 2.65 (d, J = 7.7 Hz, 2H), 2.56 (ddd, J = 12.7, 6.8, 2.3 Hz, 1H), 2.48–2.19 (m, 2H), 2.10–1.85 (m, 2H),
100 1.85–1.63 (m, 2H), 0.92 (d, J = 6.7, 3H), 0.92 (d, J = 6.7, 3H); 13C NMR (75 MHz, CDCl3) δ 197.9, 174.0, 172.7, 136.9, 134.6, 131.9, 129.7, 118.6, 116.1, 105.4, 74.8, 65.9, 62.9, 41.0, 34.1, 31.4, 27.9, 21.8, 19.2; IR (Neat Film NaCl) 3085, 2959, 2933, 2874, 1733, 1650, 1612, 1471, 1453, 1434, 1402, 1384, 1369, 1307, 1272, 1234, 1194, 1171, 1093, 1006, 968, 955, 929, 900, 864, 822, 761 cm–1; HRMS (FAB+) m/z calc'd for C20H29O4 [M+H]+: 333.2066; found 333.2052.
O
i-BuO 147
1. LDA, THF, –78 °C then
NC O
O
2. 2,3-dichloro-1-propene NaH, TBAI, THF, 0!40 °C 84% yield, 2 steps
O
i-BuO 148g
O O Cl
β-Ketoester 148g. To a solution of diisopropylamine (0.92 mL, 6.58 mmol, 1.20 equiv) in THF (27 mL) in a 100 mL round-bottom flask at 0 °C was added n-BuLi (2.56 mL, 6.30 mmol, 2.46 M in hexanes, 1.15 equiv) dropwise over 10 min. After 15 min of stirring at 0 °C, the mixture was cooled to –78 °C using an acetone/CO2(s) bath. A solution of vinylogous ester 147 (1.00 g, 5.48 mmol, 1.00 equiv) in THF (2 mL) was added dropwise using positive pressure cannulation. After an additional 1 h of stirring at –78 °C, allyl cyanoformate (0.67 mL, 6.02 mmol, 1.10 equiv) was added dropwise over 10 min. The mixture was stirred at –78 °C for 2.5 h, quenched by addition of 50% sat.
aqueous NH4Cl (8 mL), and allowed to warm to ambient temperature. The reaction was diluted with Et2O (25 mL) and the phases were separated. The aqueous phase was extracted with Et2O (3 x 25 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a pale orange oil.
101 The crude oil was dissolved in THF (8 mL) in a 100 mL round-bottom flask, cooled to 0 °C, and stirred vigorously as hexane-washed NaH (197 mg, 8.22 mmol, 1.50 equiv) was added in one portion. Evolution of gas was observed and the reaction was stirred at 0 °C for 30 min to give a yellow-orange solution. 2,3-dichloro-1-propene (1.00 mL, 10.96 mmol, 2.0 equiv) was added dropwise and the reaction was allowed to warm to ambient temperature. After 10 h, TBAI (202 mg, 0.548 mmol, 0.10 equiv) was added and the reaction was heated to 40 °C. After 41 h, the reaction was cooled to ambient temperature and quenched by addition of 50% sat. aqueous NH4Cl (10 mL). The phases were separated and the aqueous layer was extracted with Et2O (3 x 15 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 3 x 25 cm, 20:1→15:1 hexanes:EtOAc) to afford β-ketoester 148g (1.57 g, 4.61 mmol, 84% yield over 2 steps) as a yellow oil; Rf = 0.60 (4:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3) δ5.87 (dddd, J = 17.1, 10.4, 5.8, 5.8 Hz, 1H), 5.38–5.25 (m, 3H), 5.25–5.16 (m, 2H), 4.65 (dddd, J = 13.2, 5.8, 1.3, 1.3 Hz, 1H), 4.52 (dddd, J = 13.1, 5.8, 1.3, 1.3 Hz, 1H), 3.45 (ddd, J = 21.1, 9.3, 6.5 Hz, 2H), 3.04 (s, 2H), 2.71 (dddd, J = 18.2, 10.2, 3.0, 1.3 Hz, 1H), 2.62–2.47 (m, 1H), 2.39 (ddd, J = 17.2, 6.9, 2.6 Hz, 1H), 2.10–1.90 (m, 2H), 1.89–1.65 (m, 2H), 0.94 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 196.6, 174.8, 172.1, 138.1, 131.7, 118.8, 117.1, 104.9, 74.8, 66.2, 62.2, 46.1, 33.9, 30.7, 27.8, 22.6, 19.2; IR (Neat Film NaCl) 3085, 2960, 2935, 2875, 1737, 1662, 1610, 1471, 1452, 1427, 1384, 1369, 1298, 1272, 1229, 1198, 1171, 1153, 1079, 1008, 967, 930, 890, 862, 813 cm–1; HRMS (EI+) m/z calc'd for C18H25O4 [M–Cl]+: 305.1753; found 305.1742.